有机化学 ›› 2014, Vol. 34 ›› Issue (4): 797-803.DOI: 10.6023/cjoc201311030 上一篇    下一篇

研究论文

Lycogarubin C和Lycogalic Acid的化学合成及抗肿瘤活性研究

陈旺, 郝慧琳, 张晨露, 沈月毛   

  1. 山东大学药学院 济南 250012
  • 收稿日期:2013-11-18 修回日期:2013-12-02 出版日期:2014-04-25 发布日期:2013-12-13
  • 通讯作者: 沈月毛 E-mail:yshen@sdu.edu.cn
  • 基金资助:

    国家重点基础研究发展计划(973 计划,No. 2010CB833802)、国家自然科学基金(Nos. 81273384,90913024)和国家杰出青年科学基金(No. 30325044)资助项目.

Synthesis and Antitumor Activity of Lycogarubin C and Lycogalic Acid

Chen Wang, Hao Huilin, Zhang Chenlu, Shen Yuemao   

  1. School of Pharmaceutical Sciences, Shandong University, Jinan 250012
  • Received:2013-11-18 Revised:2013-12-02 Online:2014-04-25 Published:2013-12-13
  • Supported by:

    Project supported by the Major State Basic Research Development Program of China (973 Program, No. 2010CB833802), the National Natural Science Foundation of China (Nos. 81273384, 90913024) and the National Science Fund for Distinguished Young Scholars (No. 30325044).

Lycogarubin C和lycogalic acid是由Steglich和Akazawa在1994年分别独立从粘细菌Lycogala epidendrum中分离得到的海洋天然产物. Lycogarubin C有一定的细胞毒活性;lycogalic acid是螺旋-环-螺旋(Helix-Loop-Helix,bHLH) 翻译阻遏因子Hes1二聚体的抑制剂. 另外,lycogalic acid是吲哚[2,3-a]咔唑类生物碱的生物合成的关键中间体,吲哚[2,3-a]咔唑类生物碱有广泛的生物活性. 本文报道了两条合成lycogarubin C和lycogalic acid的路线. 路线一:由吲哚和吡咯出发经过8步反应以27%的收率得到lycogarubin C,其中的关键步骤是3,4-二碘-1H-吡咯-2,5-二甲酸甲酯和N-对甲基苯磺酰基-1H-吲哚-3-硼酸的Suzuki-Miyaura交叉偶联反应;路线二:由亚氨基二乙酸出发经过7步反应以25%的收率得到lycogarubin C,其中的关键步骤是N-苄基亚氨基二乙酸二甲酯和草酸二甲酯的Hinsberg反应和3,4-二三氟甲磺酸氧基-1H-吡咯-2,5-二甲酸甲酯和N-二甲基叔丁基硅基-1H-吲哚-3-硼酸的钯催化的交叉偶联反应. Lycogarubin C再经水解之后酸化得到lycogalic acid. 细胞毒实验表明lycogarubin C对MDA-MB-231,A549,HeLa和PC3肿瘤细胞有一定的生长抑制作用,进一步研究表明它具有DNA拓扑异构酶2的抑制活性.

关键词: Lycogarubin C, Lycogalic acid, Suzuki-Miyaura偶联, DNA拓扑异构酶2

Lycogarubin C and lycogalic acid were first isolated independently by Steglich and Akazawa from Lycogala epidendrum in 1994. Lycogarubin C showed a potential cytotoxic activity. Lycogalic acid is an inhibitor of Hes1 dimmer of helix-loop-helix (bHLH) transcriptional repressor factor. Lycogalic acid is also the key intermediate in the biosynthesis of indolo[2,3-a]carbazole alkaloids that exhibit broad spectrum of bioactivity. Two efficient synthetic pathways of lycogarubin C and lycogalic acid were completed in this study. The first pathway included eight steps started from the commercially available indole and pyrrole to produce lycogarubin C with an overall yield of 27%. The second pathway was completed in seven steps with an overall yield of 25%. The key reactions are palladium-catalyzed Suzuki-Miyaura coupling of bis-iodo or bis-triflate derivative and indolboronic acid derivatives and Hinsberg-type synthesis of dimethyl N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylate, respectively. Treatment of lycogarubin C with sodium hydroxide in ethanol under refluxing followed by acidification afforded lycogalic acid quantitatively. Lycogarubin C and lycogalic acid showed the antiproliferative activities against four human tumor cell lines of MDA-MB-231, A549, HeLa and PC3. Further study showed that lycogarubin C inhibited the activity of DNA topoisomerase 2.

Key words: lycogarubin C, lycogalic acid, Suzuki-Miyaura coupling, DNA topoisomerase 2